The vertebrate retina is a powerful model system for addressing mechanistic questions of how individual cell subtypes are specified during development. We have found that the homeodomain transcription factor Lhx2 regulates the development and function of retinal Muller glia. Loss of function of Lhx2 results in dramatic defects in Muller glial development. Furthermore, selective deletion of Lhx2 in mature Muller glia leads to altered expression of many genes known to be expressed in Muller glia. Furthermore, these cells becoming constitutively reactive following loss of Lhx2, mimicking the effect of injury. We propose to both identify the genes which are directly regulated by Lhx2 in mature Muller glia, and to examine the consequences of this constitutive reactivity in both uninjured and injured retina. We will determine whether mice that selectively lack Lhx2 expression in mature Muller glia demonstrate a gene expression profile that is fully characteristic of a reactive state, and determine whether Lhx2 directly represses expression of genes expressed in activated glia. Since glial reactivity has been proposed to regulate photoreceptor viability, we will conduct a detailed examination of cellular changes that occur throughout the lifespan of mutant animals following deletion of Lhx2 in mature Muller glia. Furthermore, we will determine the effects of mature glia- specific deletion of Lhx2 in models of photoreceptor injury. Finally, we will characterize any molecular signals released from Lhx2-deficient glia that regulate photoreceptor survival. PUBLIC HEALTH RELEVANCE: The vertebrate retina is a powerful model system for addressing mechanistic questions of how individual cell subtypes are specified during development. We have found that the homeodomain transcription factor Lhx2 regulates the expression of genes in retinal Muller glia, which provide support and sustenance to neurons of the retina. Furthermore, selective deletion of Lhx2 in mature Muller glia leads to these cells becoming constitutively reactive, mimicking the effect of injury. We propose to identify the molecular targets of Lhx2 in Muller glia. We will also investigate the functional consequences of Lhx2 deletion in mature Muller glia, and determine whether constitutive glial reactivity regulates photoreceptor survival following retinal injury.